Kidney Tubular Damage and Dysfunction Identify a Novel Axis of Chronic Kidney

病理研究表明，肾小管损伤、萎缩和纤维化是慢性肾脏疾病（CKD）的共同特征，并且高度预测进展到透析。已确定的CKD危险因素包括高血压和高龄与活检显示的小管损伤和纤维化有关。然而，目前CKD的临床评估仅评估肾小球功能（GFR）和肾小球损伤（蛋白尿），而不评估肾小管功能障碍或损伤。本应用的总体假设是，肾小管功能障碍和损伤是CKD发病机制和预后的可测量因素。评估肾小管功能障碍的三个指标：(1)肾小管对FGF23和PTH激素作用的抵抗；(2)酸碱平衡；(3)尿蛋白再吸收能力。FGF23和PTH是通过影响肾小管诱导磷酸尿的激素。FGF23可直接引起心脏毒性，但也可能标志着肾功能障碍。在我们的初步工作中，我们已经证明，在尿磷排泄量较低的人群中，FGF-23或甲状旁腺激素水平升高与不良后果的相关性更强。这些发现表明，将FGF23和PTH与尿磷联系起来，可以识别出肾小管对这些激素信号有抗性的个体。异常的酸碱平衡和从尿液中过滤蛋白的不完全重吸收是小管功能障碍的另一个标志，这可能对CKD患者的预后也很重要。此外，我们还研究了几种针对肾小管损伤的新型尿蛋白。在没有急性肾损伤的社区生活个体中，我们观察到尿液中两种标志物（KIM-1和IL-18）的较高浓度与CKD的突发发展、死亡和心力衰竭的风险相关，与eGFR或蛋白尿无关。总的来说，这些结果使我们假设，结合肾小管功能障碍和损伤评估的肾小管健康评估可能成为CKD评估和管理的重大进展。肾小管疾病将捕获CKD的非肾小球轴，并有助于识别CKD进展和CVD事件风险最大的患者。为了实现这些目标，我们提出了一项SPRINT试验的辅助研究-一项大型，nih赞助的多中心随机临床试验，测试强化（<120 mmHg）与标准（<140 mmHg）收缩压目标是否导致更低的CVD事件和CKD进展率。在2566名基线eGFR <60ml/min/1.73m2的SPRINT参与者中，我们将：(1)确定肾小管功能障碍和损伤与CVD事件风险的关联，(2)确定肾小管功能障碍和损伤与CKD进展的关联，(3)确定随机分配到强化血压管理组的试验是否与标准血压管理组相比，随着时间的推移减缓了肾小管功能障碍和损伤的进展。

DESCRIPTION (provided by applicant): Pathologic studies demonstrate that kidney tubule injury, atrophy, and fibrosis are common features of chronic kidney disease (CKD) and are highly predictive of progression to dialysis. Established CKD risk factors including hypertension and advanced age are associated with tubular injury and fibrosis on biopsy. However, current clinical assessment of CKD evaluates only glomerular function (GFR) and glomerular injury (albuminuria), but not kidney tubular dysfunction or injury. The overall hypothesis of this application is that kidney tubular dysfunction and injury are measurable contributors to CKD pathogenesis and prognosis. Dysfunction of the kidney tubules will be assessed by three indices: (1) renal tubule resistance to hormone actions of FGF23 and PTH; (2) acid/base homeostasis; and (3) urine protein reabsorptive capacity. FGF23 and PTH are hormones that induce phosphaturia through effects on kidney tubules. FGF23 can directly cardiac toxicity, however it may also mark kidney dysfunction. In our preliminary work, we have demonstrated that elevated levels of FGF-23 or PTH are more strongly associated with adverse outcomes among persons with concomitantly lower urine phosphorus excretion. These findings suggest that indexing FGF23 and PTH to urine phosphorus identifies individuals with renal tubules that are resistant to these hormonal signals. Abnormal acid/base homeostasis and incomplete reabsorption of filtered proteins from the urine are additional markers of tubule dysfunction that may also be important for prognosis in persons with CKD. In addition, we have investigated several novel urinary proteins that are specific to renal tubular injury. Among community-living individuals without acute kidney injury, we have observed that higher urine concentrations of two markers (KIM-1 and IL-18) are associated with incident development of CKD and risk of death and heart failure, independent of eGFR or albuminuria. Collectively, these results have led us to hypothesize that an assessment of kidney tubular health that incorporates assessments of tubular dysfunction and injury could develop into a major advance in our assessment and management of CKD. Kidney tubular disease would capture a nonglomerular axis of CKD, and could help identify patients at greatest risk for CKD progression and CVD events. To address these objectives, we propose an ancillary study to the SPRINT trial - a large, NIH-sponsored, multi-center randomized clinical trial testing whether intensive (<120 mmHg) vs. standard (<140 mmHg) systolic blood pressure targets result in lower CVD events and rates of CKD progression. Among 2,566 SPRINT participants with eGFR <60ml/min/1.73m2 at baseline, we will: (1) determine the association of kidney tubular dysfunction and injury with risk of CVD events, (2) determine the association of kidney tubular dysfunction and injury with CKD progression, and (3) determine whether randomization to intensive blood pressure management arm of the trial slows progression of kidney tubular dysfunction and injury over time compared with standard blood pressure management.